Cerebellar and Basal Ganglia Markers Underlie Neuromotor Impairments in Adults with Autism Spectrum Disorder (ASD)

项目概要/摘要 尽管被概念化为一种神经发育障碍，目前的研究主要集中在婴儿 和儿童相比，自闭症谱系障碍 (ASD) 越来越被认为是一种终生疾病， 可能对成人功能和生活质量产生不利影响。根据临床观察， 患有自闭症谱系障碍（ASD）的中老年人在衰老过程中可能特别容易患神经退行性疾病， 拟议的研究将检验小脑和基底神经节选择性地 40 至 60 岁患有自闭症谱系障碍 (ASD) 的成人中，这种现象受到干扰。而且，这种破坏与神经运动损伤有关 和运动障碍的临床症状。自由水扩散磁共振成像（FWdMRI）将 用于量化小脑小叶、齿状核、基底神经节核和轴突的神经元变性 小脑脚的完整性，以确定这些皮层下目标是否在患有自闭症谱系障碍的成人中受到破坏 相对于年龄、性别和智商匹配的对照。精准握力的功能性核磁共振（fMRI）将用于量化 皮质-皮质下大脑目标的异常激活以及这些改变是否支撑握力 ASD 中与生产相关的损害。使用敏感的神经运动测试来检测 小脑和基底神经节，我们将阐明龙伯格立场的表现程度，快步 患有自闭症谱系障碍的成年人的启动能力、坐姿平衡和目标导向的手指指向能力都会受到影响。指导者 强有力的初步数据，我们将追求三个具体目标： 目标 1) 确定结构变化 使用 FWdMRI 观察 ASD 成人的小脑和基底神经节。目标 2) 确定功能缺陷 使用运动功能磁共振成像 (fMRI) 观察自闭症谱系障碍 (ASD) 成人的小脑和基底神经节。目标 3) 确定神经运动障碍 患有 ASD 的成人。我们的团队拥有承担这一关键 R01 项目的独特资质，因为其中包括研究人员 拥有 ASD 感觉运动神经生理学、ASD 诊断、衰老和运动方面的专业知识和经验 疾病、MRI 物理和研究以及生物统计学。该提议具有科学创新性，因为它将成为 第一个在大脑、行为和神经水平上系统地量化自闭症谱系障碍中与衰老相关的神经运动问题 临床领域。该项目意义重大，因为它有望识别假定的非侵入性特征 皮质下大脑靶点导致自闭症谱系障碍（ASD）衰老。如果成功，这项工作将识别出新的大脑和 可以跟踪生物行为目标，以了解、监测和治疗自闭症谱系障碍中与衰老相关的疾病。

PROJECT SUMMARY/ABSTRACT Although conceptualized as a neurodevelopmental disorder with present research primarily focused on infants and children, autism spectrum disorder (ASD) has increasingly been recognized as a lifelong condition with the potential to have a detrimental impact on adult functioning and quality of life. Based on clinical observations that mid-to-older aged adults with ASD may be particularly susceptible to neurodegenerative diseases during aging, the proposed studies will test the central hypothesis that the cerebellum and basal ganglia are selectively disrupted in adults with ASD aged 40 to 60 years. And, this disruption is associated with neuromotor impairments and clinical signs of movement disorders. Free-water diffusion magnetic resonance imaging (FWdMRI) will be applied to quantify neuronal degeneration of the cerebellar lobules, dentate, and basal ganglia nuclei and axonal integrity of cerebellar peduncles to determine whether these subcortical targets are disrupted in adults with ASD relative to age-, sex-, and IQ-matched controls. Functional MRI (fMRI) of precision grip will be used to quantify abnormal activations of cortico-subcortical brain targets and whether these alterations underpin grip force production-related impairments in ASD. Using neuromotor tests sensitive in detecting alterations of the cerebellum and basal ganglia, we will clarify the extent to which performance of Romberg stances, quick step initiation, sit-to-stance balance, and goal-directed finger-pointing is compromised in adults with ASD. Guided by strong preliminary data, we will pursue three specific aims: Aim 1) Determine structural alterations in the cerebellum and basal ganglia in adults with ASD using FWdMRI. Aim 2) Determine functional deficits in the cerebellum and basal ganglia in adults with ASD using motor fMRI. Aim 3) Determine neuromotor impairments in adults with ASD. Our group is uniquely qualified to undertake this critical R01 project as it includes investigators with expertise and experience in sensorimotor neurophysiology in ASD, ASD diagnosis, aging and movement disorders, MRI physics and research, and biostatistics. This proposal is scientifically innovative as it will be the first to systematically quantify aging-related neuromotor issues in ASD at the levels of brain, behavioral, and clinical domains. This project is significant as it holds the promise to identify putative non-invasive traits of subcortical brain targets contributing to aging in ASD. If successful, this work will identify new brain and biobehavioral targets that can be tracked to understand, monitor, and treat aging-related conditions in ASD.